Dissecting the role of NF-kappaB signaling in ovarian cancer tumor-initiating cells

FARE Award Winner

Authors

• CD House
• CM Annunziata

Abstract

Ovarian cancer is the most lethal gynecological malignancy in the United States with high morbidity and mortality due to recurrence and chemoresistance. Our data suggest tumor-initiating cells (TICs) play an important role in disease biology. We previously showed that a subset of ovarian cancer cells depends on NF-kappaB signaling, and that expression of NF-kappaB proteins is associated with poor survival. To investigate this pathway in TICs, we designed a novel method to enrich for TICs from cell lines and patient samples by culturing non-adherent, floating cells in stem cell conditions. Preliminary data show these cells have higher stem cell marker expression, are chemoresistant, and are more tumorigenic in nude mice compared to their adherent counterparts. Given that NF-kappaB expression correlates with a poor outcome in ovarian cancer, and NF-kappaB activity supports drug resistance and tumorigenicity, we hypothesize that NF-kappaB supports a TIC program responsible for ovarian cancer relapse. Preliminary data show TIC-enriched culture conditions increased NF-kappaB expression and activity in TICs and stimulation of NF-kappaB signaling enhanced chemoresistance and stem cell marker expression. Current studies focus on dissecting the role of individual NF-kappaB proteins in TICs using inducible shRNAs to measure changes in spheroid formation, chemoresistance, tumorigenesis, and disease relapse following chemotherapy in a xenograft model. We will measure system level changes induced by these shRNAs, and identify a gene signature specific to NF-kappaB in ovarian TICs. Clarifying the nuances of NF-kappaB signaling in TICs will increase our understanding of ovarian cancer recurrence and may lead to improved therapeutic strategies.

Scientific Focus Area: Cancer Biology

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